Scientists at Ohio University are developing compounds that one day could lead to new medical treatments for disease, from cancer to diabetes

“How soon will the drug be available?” they ask. “How can we participate in clinical trials?”

For those watching a family member struggle with ovarian cancer, type 2 diabetes, or a growth hormone disorder, any information about advances in the treatment of these or any other diseases so prevalent in modern American life is a cause for hope. They scan medical news reports and academic journal articles eagerly for a sign of a path to health. It’s not uncommon for patients and their families to reach out directly to the scientists working on new drug developments.

Medical wonders have emerged from research laboratories, but the process which one Ohio University researcher aptly described as “not overnight”—can take many years, as well as much trial and error. Development of a new drug requires countless tests of different compounds in test tubes, animals, and ultimately human patients; the funding to sponsor safety and efficacy trials; and the business savvy to work with companies that have the resources to advance and promote the treatment for human use.

For the scientist, the process also requires creative thinking, hard work, and years of patience. But the possible payoff—a discovery that could be the seed of a drug that could finally help someone suffering from testicular cancer or diabetes—keeps scientists pushing toward that goal.

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In 2010, Ohio University marked two major milestones in this process that were decades in the making. In January, the Quidel Corporation announced its purchase of Diagnostic Hybrids Inc., a biotech firm founded in 1983 based on Ohio University faculty research. Today the company is a market leader in the development and distribution of cellular and molecular diagnostic kits for detecting a wide range of medical conditions. Diagnostic Hybrids, which got its start at Ohio University’s Innovation Center and is led by alumnus David Scholl, reported $38 million in revenue in 2008. It employs more than 200 at its headquarters in Athens, Ohio. Ohio University expects to receive about $40 million from the sale.

In February, a national survey of universities showed that during fiscal year 2008, Ohio University was the top public institution in the state for licensing revenue generated from its research discoveries. The university’s licensing revenue, $5.8 million, placed the institution second in Ohio only to Case Western Reserve University, a private school that reported $13.2 million. In addition, Ohio University is one of the top institutions in the nation for research return on investment, based on its royalty income received per research dollars spent ($26 million for fiscal year 2008), according to the study by the Association of University Technology Managers (AUTM).

Most of the royalty income stems from a license to the Pfizer corporation for a growth hormone antagonist (which blocks the action of growth hormone) developed by John Kopchick, a scientist with the university’s Edison Biotechnology Institute and College of Osteopathic Medicine, and former graduate student Wen Chen. The discovery became the basis for the drug Somavert, a treatment for people with acromegaly, a growth hormone disorder that can cause excessive growth of organs and bones in adults and can lead to premature death.

Ohio University has received almost $30 million in licensing revenue from Somavert to date. But like Diagnostic Hybrids, this was no overnight success story—the drug stems from a discovery made by Kopchick and colleagues in the late 1980s.

Still, the success of Somavert, Diagnostic Hybrids, and other inventions based on university research inspires several scientists at Ohio University to pursue some of the most difficult questions—and pervasive human diseases—in the lab.

Battling SuperbacteriaSteve Bergmeier & Mark McMills

It’s a nightmare for hospitals: the rise of “superbacteria” that can thwart all conventional antibiotics. And though these potent strains are on the rise, no new chemical class of anti-bacterial compounds has been developed since the 1960s.

Steve Bergmeier and colleagues are looking to nature for a solution. Bergmeier and fellow Ohio University chemistry professor Mark McMills and Nigel Priestley from the University of Montana are developing a class of new anti-bacterial compounds developed from molecules made by bacteria themselves. In the laboratory, the scientists tear the molecules apart and reassemble them in ways to design more potent agents against bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), more commonly known as a “staph infection.” MRSA can cause serious illness and even death.

Because the compounds are derived from the bacteria’s own defenses and are unique, it may take bacteria much longer to become resistant to them than conventional drugs, says Bergmeier, a professor of chemistry and biochemistry. The team is currently testing different versions of the compounds, and recently found four that work as well as conventional antibiotics.

When the researchers originally approached the National Institutes of Health (NIH) for funding for this work, the federal agency responded that their proposal sounded more like a business plan than an academic study. Taking that cue, the trio formed the biotech start-up Promiliad. The move paid off, as the researchers have had more luck pulling dollars from the federal agency’s small business technology development programs than its conventional academic research programs. By focusing on the research’s potential for commercialization and drug development, Promiliad has landed seven Small Business Technology Transfer (STTR) and Small Business Innovation Research (SBIR) grants, both designed to foster research and economic development, from the NIH in the last decade.

The Edison Biotechnology Institute also provided funding through a National Science Foundation Partnerships for Innovation grant to help develop these antibacterial compounds. In addition, the institute assisted the company in acquiring a $100,000 grant from TechGROWTH Ohio, funded by a Third Frontier grant from the state of Ohio, to test its compounds further in animal models. If the work is successful, TechGROWTH may award additional dollars. Funding from such economic development programs not only helps move basic research forward, Bergmeier says, but could help move the compounds closer to the marketplace.

“If everything works out the way you’d like it to, you potentially could have a new therapy out there that could directly benefit people,” he says. “As a scientist who is involved in whatever aspect of drug discovery, that’s an exciting thing. Academic research is rarely going to get you there. Going this route is still a long shot, but it’s more of a direct path to that.”

Bergmeier notes that turning a promising laboratory compound into a drug available for consumer use “isn’t an overnight process,” but the presence of such funding programs suggest that state and federal
agencies are committed to finding long term solutions to major health problems. “The programs support small companies— and even not so small ones—that are not going to bring in money tomorrow,” he says. “They’re a long-term investment not only on our part, but on the part of investors—the taxpayers.”

University scientists are often in a better position than researchers employed by private corporations or government agencies to take risks in their laboratories that could lead to key breakthroughs. And even failure can drive innovation, Bergmeier says, by pointing companies in other directions to solve problems.

Building a technology pipeline

To take a discovery from the laboratory to the marketplace, university inventors can rely on technical, business, and legal support from Ohio University’s technology transfer and economic development programs.

The Technology Transfer Office assists researchers with filing patents, studying the market for new inventions, and finding companies that can license and commercialize the research. Some faculty inventors choose to become entrepreneurs by licensing the technology back from the university and starting their own companies. The Innovation Center, the oldest university-based small business incubator in Ohio, provides those faculty inventors with office and laboratory space, business mentoring, and networking with investors and fellow entrepreneurs. These offices work closely with the Edison Biotechnology Institute, which provides assistance to life sciences companies and is the home of many of the university’s key life sciences technologies, as well as faculty in engineering, chemistry, health, and medical disciplines.

In the last few years, Ohio University has attracted more funding and venture capitalists to support entrepreneurship. The institution received almost $10 million in support from the Entrepreneurial Signature Program, part of the state Third Frontier Initiative. The grant created TechGROWTH Ohio, a program that provides business assistance and financial support to biotech and high-tech start-up firms in southeastern Ohio. TechGROWTH has assisted more than 250 companies and helped launch 17 start-up businesses. Athens also is now home to two venture capital groups, Athenian Ventures and Adena Ventures, that seek to support entrepreneurship in the region. In addition, the new Center for Entrepreneurship at Ohio University hopes to grow the next generation of entrepreneurs.

New targets for ovarian, testicular, head and neck cancerRathindra Bose

Though some conventional drugs can effectively treat the disease they were designed for, they also can create unpleasant side effects for the patients. The first drug developed for the treatment of ovarian and testicular cancers, cisplatin, was approved for use in 1982. Though it’s 95 percent effective, it works best during the early stages of the disease, and some patients develop a resistance to it.

Two drugs introduced later, carboplatin and oxaliplatin (which is used for colorectal cancer), overcame some of those toxicity problems, but their acquired resistance remains a major problem, says Ohio University scientist Rathindra Bose, who has been studying alternative compounds and targets for these cancers for 25 years.

Early studies in the Bose lab suggest that a new class of compounds called phosphaplatins can effectively kill ovarian, testicular, head, and neck cancer cells with potentially less toxicity and fewer side effects than those conventional drugs. The research also shows that the compounds could be effective for cancers that have become resistant to drugs. Existing drugs also can interfere with the functions of the cell’s enzymes, which lead to side effects such as hearing and hair loss and renal dysfunction.

Phosphaplatins, however, don’t penetrate the cell nucleus or attach to DNA, explains Bose, a professor of biomedical sciences and chemistry and Edison Biotechnology Institute scientist who also serves as vice president for research at Ohio University. He and his colleagues have shown that these compounds remain in the lipids and transmit a “death signal” into the interior of the cell. The compounds are created by attaching platinum to a phosphate ligand, which can readily anchor to the cell membrane.

Bose’s research, which was published in the journal Proceedings of the National Academy of Sciences and appeared as a cover story in Nature SciBx Magazine, shows that phosphaplatins can kill ovarian cells at half the dosage of conventional drugs, but are just as potent. Unlike cisplatin, which can decompose quickly and create additional toxic side effects through the decomposition products, the new compounds show no signs of degradation after seven days, he notes. “The research suggests a paradigm shift in potential molecular targets for platinum anticancer drugs and in their strategic development,” Bose says.

Preliminary tests in mice uphold the data supporting the compounds’ superior performance over existing drugs. Bose and his colleagues are continuing those tests and are seeking additional funding to advance the work. A U.S. patent has been issued on the work, one is pending, and another patent application is in preparation.

New life for growth hormone drugJohn Kopchick

In 2003, the U.S. Food and Drug Administration (FDA) approved use of the drug Pegvisomant for the treatment of acromegaly, a form of gigantism that affects about 40,000 people worldwide. The drug is based on a 1987 discovery of a growth hormone antagonist by Goll-Ohio Professor of Molecular Biology John Kopchick. Today the drug is produced and sold by the Pfizer corporation under the name Somavert, and the licensing agreement with the pharmaceutical giant has netted Ohio University almost $30 million in royalty income to date.

But that isn’t the end of Pegvisomant’s story, as any new drug can have multiple clinical applications. Because the scientific literature published in the last 20 to 30 years has pointed to a link between excessive growth hormone and cancer, Kopchick and his colleagues have explored the potential use of growth hormone antagonists as a cancer treatment.

Studies with Canadian scientist Michael Pollack and with Steve Swanson at the University of Illinois at Chicago’s Medical College suggest that blocking growth hormone can stop the growth of cancer cells. In mouse models, the growth hormone receptor antagonist reduces the progression of breast and prostate tumors and may be effective against colorectal and some brain cancers. In some cases, data show that Pegvisomant even stops metastasis of several types of cancers of the liver, Kopchick notes.

Whether to pursue clinical trials with human patients is a business decision that rests in Pfizer’s hands, Kopchick says. University researchers will probe new questions for the sake of adding to the scientific understanding of the issue, and if a new clinical use comes out of it, he says, “that’s icing on the cake.”

Like others involved in drug development, the scientist points out that turning a compound into an FDA-approved drug can take almost 20 years of work, as well as significant financial resources. Clinical trials must prove that the compounds are safe for human use, and also verify that they indeed can effectively treat patients suffering from the disease. Most compounds that enter human clinical trials are not approved as safe and efficacious drugs.

“There are so many steps where something could go wrong. You never know what you’re going to get,” he says.

Because the discovery of a drug can have such a big payoff for the inventors, institution, and the patient, scientists will continue to join the hunt.

Kopchick notes that while his research is a great case study on the successes of drug development, it also speaks to the power of discovery. His team wasn’t looking for a growth hormone inhibitor when they first began the research—they were, in fact, looking for a treatment for patients with too little growth hormone—but made a serendipitous find.

For patients, it turned out to be a powerful discovery. Not long after the FDA approved Somavert, Kopchick began to receive letters and phone calls from people with acromegaly. One woman in Ohio had tried every possible medication and surgery before finding that Somavert could control her disease.

Pancreatic cancer is a tough cancer to beat. The gold standard drug on the market for treatment, gemcitibine, extends life by only two weeks.

When Ohio University scientists Kelly McCall and Leonard Kohn unveiled laboratory studies that showed a new compound called C10 could trump that track record, their poster presentation at a cancer conference drew a long line of researchers eager to hear more. When the crowd hadn’t dispersed at the close of business, the convention center staff had to ask them to leave.

“That shows how desperate—and excited—everyone is for a potential new treatment for the disease,” says Doug Goetz, a professor of chemical and biomolecular engineering involved in the research.

Like a lot of scientists involved in drug discovery, the team didn’t set out to find a new treatment for cancer. Kohn, now a former Ohio University faculty member, originally had developed C10 to combat autoimmune diseases such as diabetes and colitis. At the Edison Biotechnology Institute, Kohn recruited Goetz, McCall, and other scientists to work on the compound, which disrupts the body’s toll-like receptors to combat the inflammation and other complications triggered by these diseases.

In laboratory studies, the team tested the compound on human tissue that included cancer cells. To their surprise, C10 was effective at slowing the growth of the cancer cells in addition to combating autoimmune diseases. Further studies revealed that some of the molecular mechanisms that play a role in pathological inflammation also play a role in cancer, McCall explains.

“Our research takes a novel approach to therapy by trying to inhibit the environmental induction of disease expression rather than our genetics, which predisposes us to diseases,” says McCall, assistant professor of endocrinology in the College of Osteopathic Medicine.

In 2009, the researchers received a $2.6 million Small Business Technology Transfer (STTR) grant from the NIH—their second in three years—through Interthyr, the company Kohn had established to commercialize the compound. The grant is funding animal studies that the scientists hope will confirm that C10 is more effective than gemcitibine.

If so, the team can pursue an Investigational New Drug application with the U.S. Food and Drug Administration (FDA). To bring a drug to market, researchers must complete 10 tests for safety and efficacy in FDA-approved labs in order to determine if there are negative side effects on the heart, liver, or other biological functions. The STTR grant can pay for most of these tests, making it a “game changer” for the project, Goetz says.

“This allows us to do a big portion of what we need to do to get us closer to market,” he says.
If the tests reveal safety issues with the compound, the team can turn to colleagues Steve Bergmeier and Mark McMills for help with finding molecular alternatives.

In the meantime, the STTR grant—which aims to foster economic development through research initiatives—is bringing jobs to Ohio. Interthyr has become a new tenant in the Innovation Center, Ohio University’s small business incubator that focuses on high-tech and biotech start-up firms. The company also is partnering with private partners around Ohio on various aspects of the research, Kohn says.

A 'Green' drug delivery system

A lot of therapeutic proteins are so small that the kidneys move them out of the system too quickly. Drug companies have added polyethylene glycol groups (compounds that can be used in medicine) to the proteins to make them bigger and last longer in the body, but as a result, the therapeutics can become less potent.

Ohio University scientists are looking to plants for a solution. Research by Marcia Kieliszewski, a professor of chemistry and biochemistry, Professor John Kopchick, Nick Okada, assistant professor of pediatrics in the College of Osteopathic Medicine, and Jay Xu, now at Arkansas State University, suggests that by exploiting features of glycoproteins found in plants, drug delivery can become less expensive, more effective, and longer lasting, and involve fewer side effects. Their method frequently increases the yield of these biological compounds from plants, which has been a barrier to using plants in the past.

The scientists designed a suite of drug delivery technologies based on the glycoproteins that has broad applications for peptide- and protein-based therapeutics for a variety of medical ailments—from diabetes and cancer to rheumatoid arthritis and intestinal bowel disease.

The Ohio University Technology Transfer Office is currently in discussions with firms seeking to license this technology in various markets and applications, says Director Bryan Allinson.

“Given the breadth and depth of applications, we envision that there could be either a number of potential licensees—or alternatively, a single ‘rainmaker type’ licensee—that could bring these technologies to market for the benefit of society and betterment of patient health,” he says.